Dosimeters were developed in order to provide a means of reliably and reproducibly measuring the extent, degree, and distribution of penetration of radiation into media of interest. “Dosimeter” is defined herein as a device designed to undergo changes upon exposure to penetrating radiation, the changes being detectable and quantifiable by the practitioner, and the changes being indicative of the amount and distribution of the incident radiation contained in that exposure. “Penetrating radiation” is defined herein as electromagnetic energy having the form of particles or waves which permeates to some extent a medium of interest in the application. Energy deflected, reflected, or otherwise repelled from the surface of the medium is not penetrating; whereas energy absorbed, transmitted, or in any other sense passing into or through the medium is defined as penetrating. Penetrating radiation may be of natural origin (including, but not limited to sunlight, alpha particles, beta particles, gamma radiation, and other examples of the electromagnetic spectrum) or may be manmade (including, but not limited to neutron radiation, proton radiation, photon radiation, e-beam radiation, high-intensity x-radiation, carbon ion beam radiation, UVA light (400 nm–320 nm), UVB light (320 nm–290 nm), UVC light (290 nm–100 nm), and laser light). It has long been of importance to monitor the extent, degree and distribution of the penetration of this sort of radiation into various media in order to measure and assess the effects of exposure upon materials and humans.
Dosimeters have been known for over five decades. (See Day, M. et al., Nature 1950; 166:146–147 Day, M., Phys Med Biol. 1990; 35:1605–1609; Hoecker, F. and Watkins, I., Int J Appl Rad Iso. 1958; 3:31–35; The radiochromic effect and its chemical mechanisms have been studied as a means of radiation dosimetry (see McLaughlin, W. L., Trans. Am. Nucl. Soc. 1968; 11:460; McLaughlin, W. L. and Kosanic, M., Int. J. Appl. Radiat. Isot. 1974; 25:249; McLaughlin, W. L. et al., Riso Report M-2202, Riso National Lab., Roskilde, Denmark, 1979; Kosanic, M. M. et al., Int. J. Appl. Radiat. Isot. 1977; 28:313; Bobrowski, K. et al., J. Phys. Chem. 1985; 89:4358.). Previously it was shown that radiation can be monitored by exposure of two-dimensional films, plates, or flat composites made from, inter alia, photographic emulsions (silver halide on cellulose and advancements on this art: Becker, K., Solid State Dosimetry, CRC Press, Cleveland, Ohio, 1973, pp. 231–237), thermoluminescent materials (lithium fluoride formulations and advancements on this art, McKinlay, Thermoluminescence Dosimetry, Chapter 4, Adam Hilger Ltd., 1981), phosphate glass, phosphor-containing materials, gels or films containing radiochromic dyes (McLaughlin, W. et al., Radiat. Phys. Chem 198; 18:987–989). Sunlight dosimeters have been described, see Petkov, I. and Nunzi, J. in Third Internet Photochemistry and Photobiology Conference, Nov. 24–Dec. 24 2000; Diffey, B. Photochem. Photobiol. 1994; 60:380–382; Parisi, A. et al., Phys. Med. Biol., 1997; 42:77–88; Diffey, B. et al., Br. J. Dermatol., 1997; 97:127–130; Rahn, R. and Lee, M., Photochem. Photobiol. 1998, 68:173–178.
Examples of “reporter compounds” of the invention. Leuco dyes are defined herein as compounds which undergo a structural change: 1) upon the absorption of penetrating radiation, or 2) by the action of a local decrease in pH brought about by the liberation of H+ ions caused by the absorption, by the medium or by an added activator molecule, of penetrating radiation, or 3) or by the action of radical species generated by the absorption of radiation by the medium or by an added activator molecule. The structural change gives rise to a corresponding change in one or more optical properties of the leuco dye. The change or changes in optical properties can be, but is not limited to, a shift in the absorption spectrum in the IR or the UV-visible range, for example such that the “leuco” or starting structure is colorless and the radiation-transformed structure is colored; or the induction of fluorescence or phosphorescence. Examples of leuco dyes are photochromic dyes, radiochromic dyes, pH-indicating dyes, and radiographic dyes. Leuco dye systems are well known in the literature. Leuco dyes in their reduced leuco form, when properly chosen, can form the basis of color image forming systems. Radiographic imaging based on crosslinking of organic molecules by absorbed radiation has been described (Kosar, J., Light-Sensitive Systems, Wiley, N.Y., 1965; pp. 158–193, MacLaughlin, W. L., in Manual on Radiation Dosimetry, Holm, N. and Berry, R., eds., Dekker, N.Y., 1970, pp. 129–177). Use of tetrazolium dyes in radiographic imaging in colloids and aqueous gels has been reported Zweig, J. I. et al., Cancer Treatment Rep. 1977; 61:419–423). Leuco dye systems are further discussed in Kosar's Light Sensitive Systems, pp. 367, 370–380, 406, (1965), Wiley and Son, Inc., N.Y.; and Chemistry and Applications of Leuco Dyes R. Muthyala, ed., (1997), pp. 1–3, 47–53, 67–74, 97–98, 125–127, 159–162, 207–208, Plenum Press, N.Y. Leuco dyes in solution have been used for dosimetry (Farahani, M. et al., Appl. Radiat. Isot. (Int. J. Radiat. Appl. Instrum. Part A) 1990; 41:5–11. Leuco dyes have been incorporated in polymer films and evaluated as two-dimensional dosimeters: Sidney, L. N. et al., Radiat. Phys. Chem. (Int. J. Radiat. Appl. Instrum., Part C) 1990; 35:779–782; Khan, H. M. et al., Radiat. Phys. Chem. (Int. J. Radiat. Appl. Instrum., Part C) 1991; 38:395–398; and U.S. Pat. Nos. 2,936,276; 3,370,981; 3,609,093; 3,710,109; 3,743,846; 3,903,423; 4,829,187; and 5,117,116. Films containing dyes or dye precursors have been employed as routine dosimeters for food irradiation, sterilization of medical products, and radiation processing (MacLaughlin, W. L. in Sterilization by Ionizing Radiation, Gaughran, R. and Goudie, A., eds., Multiscience, Montreal, Vol. I, 1974; Humphries, K. and Kantz, A. Radiat. Phys. Chem. 1977; 9: 737; Kantz, A. and Humphries, K., Radiat. Phys. Chem. 1979; 14: 575). Leuco dyes in organic solvents have been irradiated using halocarbons as activators. See MacLachlan, A., J. Phys. Chem. 1967; 71:718–722; Miyaji, T., et al., J. Photopolym. Sci. Technol. 2001; 14:225–226; UK Patent Application GB 2182941A). pH-Indicating dyes have been admixed with polyvinyl chloride to produce polymers which give a color reaction upon irradiation due to HCl liberated by a radiolytic process (U.S. Pat. Nos. 3,743,846 and 3,899,677; Ueno, K., Radiat. Phys. Chem. 1988; 31:467–472). Leuco dyes formulated with photo acid generators in solvent systems have also been described. See Tokita, S., et al., J. Photopolym. Sci. Technol. 2001; 14:221–224.
Another form of radiochromic dye based on polydiacetylenes has been described. In this system, a colorless dispersion of monomeric species is polymerized upon exposure to radiation, resulting in the development of colored regions, or regions having otherwise altered optical properties. Film formulations utilizing this technology have been commercialized (GafChromicTM Films, International Specialty Products, Wayne, N.J.). A review of dosimeters formed by these films has appeared (Niroomand, A. et al., Med. Phys. 1998; 25:2093–2115).
It was found that by stacking, laminating, layering, or organizing dosimeter films into a three-dimensional shape, a heterogeneous system could be fabricated which approximates a 3D dosimeter. U.S. Pat. Nos. 5,661,310; 5,430,308; 5,130,065; 5,123,734; 5,104,592; 5,096,530; 5,076,974; 5,059,359; 5,059,021; 5,058,988; 5,015,424; 4,999,143; 4,996,010; 4,929,402; 4,394,737 and 4,575,330 disclose variants of this technology. Some of the disadvantages of utilizing multiple thin films or plates to measure penetrating radiation in a three-dimensional volume are: difficulty in designing, manufacturing, assembling, positioning and securing several discrete films or plates; limitations in size and shape of the fabricated dosimeter due to its inherent composite nature; difficulty and time-consumption of disassembly of the fabrication, identification of the original location of each film or plate, and scanning data from each distinct film or plate; inherent error in measurement due to the unavoidable heterogeneity of the dosimeter due to its composite nature.
Another approach to the fabrication of a 3D dosimeter uses the employment of aqueous gels containing materials to interact with incident penetrating radiation to give species which could later be detected and quantified. Dosimeters containing ferrous salts (“Fricke solution”) have been utilized in mapping penetrating radiation (Fricke, H. and Hart, E. “Chemical Dosimetry” in Radiation Dosimetry Vol. II, Chapter 12, Attix, F. et al. ed., Academic Press, New York, 1966). Aqueous gels containing Fricke dosimeter solution in combination with magnetic resonance imaging (MRI) techniques have been disclosed (Gore, J. C., et al., Phys. Med. Biol. 1984; 29:1189–1197;). In this approach, the radiation-induced oxidation of ferrous to ferric ions in solution could be detected by a change in the water proton spin relaxation times, T1 and T2, and the changes were large enough to be mapped with high spatial resolution by MRI when the Fricke solution was dispersed in a gelatin or agarose gel. (Gore, J. C., et al., Mag. Res. Imaging, 1984; 2:244; Schulz, R. J., et al., Phys. Med. Biol. 1990; 35:1611–1622). A similar dosimeter based on ferrous sulfate and agarose gel was described. (See Olesson et al., Appl. Radiat. Isot. 1991; 42:1081–1086; Appleby, A. and Leghrouz, A., Med. Phys. 1991; 18:309–312.) Some disadvantages associated with the use of this approach are the rapid diffusion of oxidized ions resulting in an inherent limitation to stability and resolution of the image, the necessity for relatively high dose rates and long radiation times, and unpredictable behavior in small volumes.
New Fricke systems with improved diffusion parameters have been developed. (See Chu, K et al., Phys. Med. Bull. 2000; 45; 955–969.) Reviews of MRI-mediated dosimetry are provided in MacDougall ND, et al., Phys Med Biol. 2002; 47(20):R107–21 and in McJury, M. et al., Br. J. Radiol. 2000; 73(873):919–29.
Another conventional approach was aqueous gels containing materials to interact with incident penetrating radiation relates to the use of a composition including droplets of superheated liquid encapsulated in a host gel. U.S. Pat. Nos. 4,143,274 and 4,350,607 disclose a radiation detector and dosimeter which is based on the fact that a sufficiently finely-dispersed liquid suspended in a host liquid of high viscosity or gel is stable at temperatures above its normal boiling point for long periods of times. Radiation and particularly neutron radiation of sufficient energy and intensity, upon coming in contact with such droplets can trigger volatilization. The volume of vapor evolved then serves as a measure of radiation intensity and dosage. Some disadvantages of utilizing such a dosimeter include the difficulty in manufacture wherein the superheated liquid is gaseous at room temperature; the limitation that high-energy radiation, e.g. neutron radiation, is necessary to affect volatilization; the inherent low resolution potential of the measurement of gas volumes.
Still another approach utilizing uniformly dispersed droplets of a very high vapor pressure liquid within an aqueous gel is described in U.S. Pat. No. 4,779,000 which discloses a dosimeter for gamma rays, microwaves, and other low linear energy transfer (LET) radiation. Upon interaction with low-level radiation the droplets “explode” into volatilized gas, and observation of bubbles in the medium serves as detection. In another approach, a 3D dosimeter was fabricated from an aqueous gel containing molecules which polymerize with each other in the presence of radiation, thus forming a detectable and quantifiable image. U.S. Pat. Nos. 5,321,357 and 5,633,584 disclose systems in which soluble monomers are induced to polymerize only in those portions of the dosimeter experiencing radiant or mechanical energy. The resulting polymeric portions induce a change in the relaxation rate of nearby water molecules, allowing visualization and quantitation by MRI. Some disadvantages accompanying use of this invention include the potentially serious toxicity of components used to prepare the article, difficulties in the manufacture wherein oxygen must be necessarily excluded, and the need for expensive MRI instrumentation for the interpretation of results.
Other systems have been disclosed in which a 3D dosimeter has been fabricated utilizing a polymeric matrix containing therein materials which are altered in their optical properties through exposure to incident penetrating radiation. U.S. Pat. Nos. 5,319,210 and 5,498,876 provide a dosimetry method characterized by the steps of storing information in a three dimensional optical memory element, then exposing the optical memory element to neutron or other high LET radiation to alter the information stored in the optical memory element as a function of the radiation to which the optical memory element is exposed, and then retrieving the altered information from the optical memory element for subsequent analysis. The altered information is used to provide a measure of both the radiation dose and energy. Some disadvantages associated with the practice of this invention for 3D dosimetry include the necessity and limitations of obtaining a pre-formulated commercial polymer doped with light-sensitive chemical; difficulty in utilizing the process wherein the dosimeter is exposed by high-energy radiation in a separate process subsequent to the capture of data in the optical memory unit; the need for a third process to retrieve altered information in order to measure and quantify the original radiative event(s). A similar system for optical storage of data in three dimensions was described. (See Parthenopoulos, D. and Rentzepis, P., Science 1989; 245:843–845.) U.S. Pat. No. 6,621,086 relates to utilizing color-forming materials imbedded in an aqueous gel which, upon exposure to radiation, form permanent insoluble colored areas to be used for quantification of the original radiation dose levels. Some of the disadvantages of utilizing this invention include the limitation of employing aqueous gels, the high relative cost of the color-forming tetrazolium salts, and the relative insensitivity of the method. A 3D data storage system is disclosed in U.S. Pat. No. 4,288,861 wherein active photoreactant molecules dispersed in a fluid media are simultaneously or sequentially excited by two discreet optical beams trained at a target location within the media, giving rise to a photochemical reaction which produces physical or refractive index inhomogeneities. The data is scanned in a second operation.